WO2011107617A1 - Composition pharmaceutique liquide d'ibuprofène et de codéine à administrer par voie orale, son procédé de préparation et son utilisation - Google Patents

Composition pharmaceutique liquide d'ibuprofène et de codéine à administrer par voie orale, son procédé de préparation et son utilisation Download PDF

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WO2011107617A1
WO2011107617A1 PCT/ES2010/000078 ES2010000078W WO2011107617A1 WO 2011107617 A1 WO2011107617 A1 WO 2011107617A1 ES 2010000078 W ES2010000078 W ES 2010000078W WO 2011107617 A1 WO2011107617 A1 WO 2011107617A1
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Prior art keywords
codeine
ibuprofen
composition according
pharmaceutically acceptable
salt
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PCT/ES2010/000078
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English (en)
Spanish (es)
Inventor
Ana María JIMÉNEZ REDONDO
Ángel Muñoz Ruiz
Nuria SANZ MENÉNDEZ
Femando Martinez-Alzamora Garcia
Antonia GÓMEZ CALVO
Gonzalo HERNÁNDEZ HERRERO
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Farmalider, S.A.
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Application filed by Farmalider, S.A. filed Critical Farmalider, S.A.
Priority to PCT/ES2010/000078 priority Critical patent/WO2011107617A1/fr
Priority to GB1215436.5A priority patent/GB2490840B/en
Publication of WO2011107617A1 publication Critical patent/WO2011107617A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a new liquid pharmaceutical composition containing ibuprofen in the form of a salt formed with a basic amino acid and codeine or a pharmaceutically acceptable codeine salt, for oral administration.
  • the invention relates to a process for the preparation of said liquid pharmaceutical composition, as well as its use, preferably in pediatrics, for the manufacture of a medicament useful in the treatment of moderate to severe pain, inflammation, fever and / or other medical conditions in which ibuprofen and / or codeine are traditionally used, mainly as an analgesic.
  • Ibuprofen salts with basic amino acids have been known at least since 1976, when Spanish patent ES 435416 was published where a procedure for the preparation of an ibuprofen salt with L-arginine and a salt of ibuprofen with L-lysine.
  • Ibuprofen is a non-steroidal anti-inflammatory drug (in English "NSAID", in Spanish "NSAID") that is used in medicine for its analgesic, antipyretic and anti-inflammatory activity.
  • Solid and liquid pharmaceutical forms containing ibuprofen as active ingredient have been described in the state of the art. So by for example, in the PCT patent application WO-A-95/00134 a liquid pharmaceutical composition for oral administration containing ibuprofen, arginine, sweetening agents, preservatives and water as solvent is described. Said composition has an ibuprofen content of at least 200 mg / ml and must be diluted at the time of use.
  • Codeine is an alkaloid that was isolated in 1830 from the opium plant. Although it can be obtained by extracting said plant, it is mostly obtained by morphine methylation.
  • Different codeine salts are known, for example their hydrochloride, sulfate and phosphate. Codeine and its salts find their application in medicine for their analgesic, antitussive and antidiarrheal properties.
  • European patent application EP-A-0388125 describes that the combination ibuprofen and codeine has been known since the early 1980s and that this combination has an analgesic effect superior to that of ibuprofen or codeine alone.
  • ibuprofen and codeine can interact when they are present in the same pharmaceutical composition, said interaction being able to affect the stability of these active ingredients.
  • codeine phosphate and its degradation products and impurities by capillary electrophoresis describe an ibuprofen and codeine ester as a probable degradation product of those pharmaceutical combinations that contain both active ingredients.
  • EP-A-0159852 a composition of ibuprofen and codeine is described which is directly compressible.
  • codeine is granulated and separately from ibuprofen, together with polyvinylpyrrolidone and lactose, to avoid intimate contact between the two active components, contact that can adversely affect their stability.
  • the wet wet granulation of ibuprofen and codeine salts leads to the formation of colorations during said process and in the subsequent drying of the granulate.
  • Bilayer tablets are described in European patent applications EP-A-0220805 and EP-A-0535841 where, in order to avoid the interaction between ibuprofen and codeine, both active ingredients are found in separate layers.
  • European patent application EP-A-0274845 describes a stable solid pharmaceutical composition of ibuprofen and codeine containing an effective amount of carboxymethyl cellulose calcium salt. It is indicated that the presence of such a disintegrating agent confers stability to the compositions, while the presence of other different disintegrating agents leads to the formation of colorations when the compositions are stored at a temperature of 50 ° C.
  • ibuprofen is substantially suspended, as described in European Patent Application EP-A-0413171, where pharmaceutical compositions are developed for the treatment of serious pain states.
  • the object of the present invention is a liquid pharmaceutical composition for oral administration comprising ibuprofen in the form of a salt with a basic amino acid and codeine or a codeine salt. Also part of the object of the invention is a process for preparing said pharmaceutical composition.
  • composition preferably in pediatrics, for the manufacture of a medicament for the oral treatment of moderate to severe pain, inflammation, fever and / or other ailments of those traditionally relieved by buprofen and / or codeine.
  • An object of the present invention is a liquid pharmaceutical composition for oral administration comprising: - buprofen and a basic amino acid selected from the group consisting of arginine, lysine and mixtures thereof, in a molar ratio ibuprofen: amino acid between 0.9: 1 and 1, 1: 1;
  • - codeine or a pharmaceutically acceptable codeine salt and - at least one pharmaceutically acceptable excipient where the content of buprofen is equal to or greater than 20 mg / ml and the content of codeine or a pharmaceutically acceptable codeine salt is equal to or greater at 0.92 mg / ml.
  • liquid forms generally have a better bioavailability than solid forms, because the active substance is already dissolved when it reaches the stomach, which translates into a rapid onset of pharmacological action.
  • Liquids can be easily administered to children or people unable to swallow capsules or tablets and provide an excellent vehicle for uniform administration of drugs.
  • liquid pharmaceutical composition means that the composition is fluid at room temperature and, in general, has a viscosity of less than 5,000 cps at a temperature of 20 ° C.
  • Ibuprofen is a compound that has a chiral carbon atom in its molecule and, consequently, has two enantiomers. It is known that in medicine mainly racemic ibuprofen is used, that is (RS) -ibuprophen. It is also known that the active enantiomer is the enantiomer having the S configuration in the chiral center, that is (S) -ibuprofen. However, the other enantiomer, (R) -ibuprofen, with the R configuration in the chiral center, also contributes to the pharmacological activity of racemic ibuprofen, since it is partially converted to the enantiomer (S) in the body. In the context of the present invention, the term “ibuprofen” refers interchangeably to racemic ibuprofen (RS), as well as to (S) - buprofen and (R) -ibuprofen.
  • the ibuprofen used in the pharmaceutical composition of the present invention is selected from the group consisting of (RS) -ibuprofen and (S) -ibuprofen.
  • Ibuprofen can be prepared according to the procedure described in patent application GB-A-971700. The resolution of ibuprofen in its enantiomers is described in the article by Brushan et al., Biomed. Chromatogr., 1998, 12, 309.
  • the amount of ibuprofen present in the composition of the invention is equal to or greater than 20 mg / ml, preferably equal to or greater than 50 mg / ml, especially equal to or greater than 100 mg / ml, especially preferably equal to or greater than 150 mg / ml, in particular equal to or greater than 200 mg / ml and with particular preference is equal to 200 mg / ml.
  • Basic amino acids preferably equal to or greater than 100 mg / ml, especially preferably equal to or greater than 150 mg / ml, in particular equal to or greater than 200 mg / ml and with particular preference is equal to 200 mg / ml.
  • the composition of the invention comprises a basic amino acid selected from the group consisting of arginine, lysine and mixtures thereof.
  • Said amino acids have in their structure at least one additional amino group which gives them a basic character, so that the aqueous solutions of said amino acids have a pH in the alkaline range.
  • Many amino acids are available in form D or form L, which is the natural one.
  • the terms "arginine” and lysine "refer to form D, form L or mixtures of both forms L and D.
  • the basic amino acid arginine is used in the composition of the invention and in particular the naturally occurring amino acid L-arginine.
  • the ibuprofen: basic amino acid molar ratio is between 0.9: 1 and 1, 1: 1, preferably between 0.92: 1 and 1, 07: 1 " , especially between 0.95: 1 and 1: 05: 1, with special preference between 0.98: 1 and 1, 02: 1 and in particular is 1: 1.
  • the pH of the liquid composition obtained is between 7 and 8.
  • the pH can be adjusted within this range by means of the use of corrective agents well known to those skilled in the art.
  • the previously formed ibuprofen arginine or lysine salts can also be used.
  • Said salts can be prepared, for example, in accordance with the procedure described in Spanish patent ES435516.
  • the composition of the present invention comprises codeine or a pharmaceutically acceptable codeine salt.
  • codeine refers to codeine base or a pharmaceutically acceptable salt of codeine and the term “pharmaceutically acceptable salt of codeine” also includes the hydrates and solvates thereof.
  • the pharmaceutically acceptable codeine salt may be selected from the group consisting of hydrochloride, iodhydrate, hydrobromide, bitartrate, citrate, acetate, sulfate and phosphate.
  • codeine salt is used, in particular codeine phosphate hemihydrate.
  • the amount of codeine or the pharmaceutically acceptable codeine salt present in the composition of the invention is equal to or greater than 0.92 mg / ml, preferably equal to or greater than 2.5 mg / ml, especially equal to or greater than 3 , 0 mg / ml, especially preferably equal to or greater than 10 mg / ml and in particular is 10 mg / ml.
  • the amount of codeine or the pharmaceutically acceptable salt of codeine may reach 30 mg / ml.
  • the weight ratio between ibuprofen and codeine or the pharmaceutically acceptable codeine salt is not critical, and different proportions can be designed between them to define compositions according to the invention with different degrees of analgesic potency.
  • compositions containing 200 mg / ml of ibuprofen and 30 mg / ml of codeine phosphate hemihydrate, or 200 mg / ml of ibuprofen and 10 mg / ml can be prepared of codeine phosphate hemihydrate, or 50 mg / ml of ibuprofen and 3.17 mg / ml of codeine phosphate hemihydrate, always maintaining the proportions of active ingredients mentioned above.
  • compositions of the invention include at least one pharmaceutically acceptable excipient, which can be selected from the group consisting of preservatives, flavorings, flavorings, sweeteners and / or mixtures thereof.
  • preservatives that can be used in the pharmaceutical composition of the invention are those selected from the group consisting of domiphene bromide, butylparaben, propylparaben, ethylparaben, methylparaben, benzyl alcohol, sodium acetate, glycerin, xylitol and / or mixtures of the same, the preservatives selected from the group consisting of domiphene bromide, butylparaben, propylparaben, ethylparaben, methylparaben and / or mixtures thereof being especially preferred.
  • the pharmaceutical composition of the invention includes, as a preservative, domifene bromide, because it has a good antimicrobial efficacy in the pH range in which the composition of the invention is found.
  • the amount of domifen bromide as a preservative present in the composition of the invention is between 0.05 mg / ml and 0.5 mg / ml, preferably between 0.07 mg / ml and 0.2 mg. / ml and especially between 0.09 mg / ml and 0.11 mg / ml.
  • Alkylparaben derivatives can be used alone or in combination to obtain greater antimicrobial effectiveness. Such compounds are commercially available in acidic or salt form, so that they can be used in any of these presentations.
  • the amount of methylparaben is between 1.2 mg / ml and 2.0 mg / ml, preferably between 1.4 mg / ml and 1.8 mg / ml and especially between 1.5 mg / ml and 1.7 mg / ml; and the amount of propylparaben is generally between 0.12 mg / ml and 0.26 mg / ml, preferably between 0.15 mg / ml and 0.23 mg / ml and especially between 0.18 mg / ml and 0 , 20 mg / ml.
  • flavorings sodium chloride, ethylmaltol, ethyl vanilla, vanilla and menthol can be mentioned.
  • flavorings are mint aroma, caramel aroma and lemon aroma, although any other suitable aroma may also be present. Said aromas can be found commercially in the form of mixtures with other substances to facilitate their dosage.
  • caramel aroma may contain flavoring substances identical to natural ones, natural flavoring substances, maltodextrin, sugar, vegetable oil, silicon dioxide and lecithin.
  • the mint aroma may contain natural flavoring preparations, natural flavoring substances, flavoring substances identical to natural ones, maltodextrin, modified corn starch, glycerin triacetate and pulegone.
  • sweeteners that may be present in the composition of the invention are those selected from the group consisting of maltitol, sucrose, dextrose, fructose, glucose, glycerin, inulin, isomalt, lactitol, maltose, maltol, mannitol, sucralose, trehalose, xylitol, propylene glycol, sorbitol, sodium saccharin, thaumatine, sodium cyclamate, and / or mixtures thereof.
  • a sweetener selected from the group consisting of maltitol, sucrose, glucose, thaumatine, sodium saccharin and / or mixtures thereof is used; in particular the Sweetener is selected from the group consisting of maltitol, sodium saccharin, thaumatine and / or mixtures thereof.
  • composition of the present invention pharmaceutically acceptable excipients can be used in solid or liquid form.
  • maltitol can be found commercially in solid form or in the form of an aqueous solution containing between 68% and 85% by weight of maltitol.
  • Physico-chemical properties of excipients as well as the name of the commercial products under which they are marketed, features can be found in the book of RC Rowe et al, "Handbook of Pharmaceutical Excipients", 4th edition, Pharmaceutical Press, London , 2003 [ISBN: 0-85369-472-9].
  • liquid pharmaceutical composition of the present invention it comprises the following components:
  • this composition additionally includes flavoring agents.
  • liquid pharmaceutical composition of the invention comprises the following components: - 200 mg / ml ibuprofen,
  • this composition additionally includes flavoring agents.
  • the pharmaceutical composition of the present invention is substantially aqueous. This means that the solvent thereof is substantially water and that it is a composition substantially free of solvents other than water. While it is not excluded that some of the pharmaceutically acceptable excipients that may eventually be part of said composition may include some water miscible solvent.
  • 90% by weight of the solvents present in the composition of the invention is water, which can reach up to 95% by weight or up to 99% by weight.
  • Another object of the invention is a process for preparing the liquid composition of ibuprofen and codeine of the present invention, a process comprising the steps of: a) dilute the ibuprofen salt with the basic amino acid in a part of the water,
  • step b) add the codeine or the pharmaceutically acceptable salt of codeine and at least one pharmaceutically acceptable excipient to the solution obtained in step a), stir until complete dissolution and adjust with water to the final volume, or alternatively c) dissolve the codeine or the pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient in a part of the water,
  • step d) add the ibuprofen salt with the basic amino acid in the solution obtained in step c) and stir until completely dissolved,
  • step f) add ibuprofen to the dispersion obtained in step f) and stir until completely dissolved
  • step g add the codeine or the pharmaceutically acceptable salt of codeine and at least one pharmaceutically acceptable excipient to the solution obtained in step g), stir until completely dissolved and adjust with water to the final volume, or alternatively i) dissolve the codeine or pharmaceutically acceptable codeine salt and at least one pharmaceutically acceptable excipient in a portion of the water,
  • step j) add ibuprofen to the dispersion obtained in step j) and stir until completely dissolved and
  • the ibuprofen salt with the basic amino acid is diluted in a part of water equivalent to half the volume of the manufacturing batch; alternatively, the basic amino acid is dispersed in a part of the water equivalent to half the volume of the manufacturing batch; alternatively, the codeine or the pharmaceutically acceptable salt of codeine and the at least one acceptable excipient are dissolved in a part of the water equivalent to half the volume of the manufacturing batch.
  • the previous dispersion of the basic amino acid provides an appropriate alkaline pH that facilitates the subsequent dissolution of ibuprofen.
  • the liquid composition of the invention obtained by the process of the invention is a substantially transparent solution.
  • any precipitate that could have formed during the manufacturing process can be separated by filtration or centrifugation. Therefore, it is preferred that after the addition of the codeine or the pharmaceutically acceptable salt of codeine, and of the at least one pharmaceutical excipient, is sufficiently stirred to achieve a solution after the addition of each new component.
  • the pharmaceutical composition of the invention includes several excipients, in the process of the invention, after the addition of each of them, the mixture is preferably stirred until it is completely dissolved.
  • step b) of the process of the invention can be added in step b) of the process of the invention or alternatively after step d) and before filling with water to the final volume (step e)) or alternatively in step h) or alternatively, after from stage k) and before completing with water to the final volume (stage I))
  • the process of the invention for the preparation of the pharmaceutical composition of the invention can be carried out at a temperature between 15 ° C and 50 ° C, preferably at a temperature close to room temperature.
  • the excipients can be added in solid form or in the form of a substantially aqueous solution, previously prepared in a separate container with a part of the water that forms part of the formulation.
  • a substantially aqueous solution previously prepared in a separate container with a part of the water that forms part of the formulation.
  • foam can be formed by adding said preservative in powder form to the aqueous solution of the pharmaceutically acceptable codeine salt. Therefore, it is preferable to prepare a solution of domifene bromide in a part of the water of the formulation before proceeding with its addition to said solution.
  • the process of the invention for preparing the composition of the invention includes the step of completing with water to a final volume, a stage well known to the person skilled in the art and which refers to adding sufficient water to the container where the preparation of the composition has been carried out to obtain the desired concentration of active ingredients.
  • the pharmaceutical composition of the invention was subjected to stability tests under the following conditions of temperature and relative humidity (H.R.):
  • the liquid composition of the invention exhibited good stability and the contents of ibuprofen and codeine remained substantially unchanged after 36 months of storage at 25 ° C and under a relative humidity of 60%, at 30 ° C and under a relative humidity of 65 %, as well as after 6 months at a temperature of 40 ° C under a relative humidity of 75% and after 6 months under refrigeration at a temperature between 5 o C and 8 o C. At this temperature no appearance of some turbidity or precipitates.
  • the results corresponding to stability are presented in the Examples.
  • the content of active ingredients present in the composition of the invention can be analyzed by means of HPLC (high performance liquid chromatography) techniques, well known to the person skilled in the art, and adjusting the operating conditions by means of routine laboratory tests of analysis of pharmaceutical active ingredients.
  • the pharmaceutical composition of the invention is stable even when it includes appreciable amounts of ibuprofen and codeine dissolved in a substantially aqueous liquid composition.
  • the composition of the invention was also subjected to a photostability test, observing that the contents of ibuprofen and codeine remained substantially unchanged in the bulk solution after said test.
  • the photostability test was carried out in accordance with the specifications described in the document of the ICH (International Conference on Harmonization) according to Stability Testing: Photostability testing of New Drug Substances and Products Q1B. The results of this test are presented in the Examples section.
  • Also part of the object of the invention is the use of the pharmaceutical composition of the invention, preferably in pediatrics, for the manufacture of a medicament for the oral treatment of moderate to severe pain, inflammation, fever and / or other medical conditions. They can be relieved with ibuprofen and / or codeine. Conditions that can be relieved with ibuprofen include, for example, Alzheimer's disease, arthritis and primary dysmenorrhea.
  • the pharmaceutical composition of the invention is characterized by its high efficacy and the rapid onset of the pharmacological effect, so it is especially suitable as an analgesic to quickly relieve pain.
  • the pharmaceutical composition of the invention can be administered diluted in a liquid at the time of use, for example in water.
  • the dose to be administered to the subject may vary according to his body weight, the indication and the severity of the condition.
  • the dose of the composition of the invention to be administered to the subject orally is that which allows a quantity of buprofen of between 100 and 800 mg to be given every 4 to 6 hours, preferably between 200 and 400 mg, with the maximum daily dose between 800 and 1,200 mg of ibuprofen. In some cases, a maximum daily dose of 2,400 mg of ibuprofen can be reached.
  • the pharmaceutical composition of the invention is also suitable for pediatric use.
  • the pediatric dose of ibuprofen to be administered to the subject orally through the composition of the invention is between 5 mg / kg and 10 mg / kg of buprofen every 4 to 6 hours.
  • the pediatric dose of codeine to be administered orally to the subject through the composition of the invention is between 0.5 and 1 mg / kg every 4 to 6 hours, with a maximum of 60 mg / dose, reaching some cases at a daily dose of 120 mg.
  • the oral oral liquid formulation thus obtained has the following composition:
  • Purified water is.
  • the concentrated liquid composition thus obtained contained 200 mg of ibuprofen per ml, 10 mg of codeine phosphate hemihydrate per ml, the solids content being greater than 400 mg per ml.
  • This composition exhibited high stability and the contents of ibuprofen and codeine phosphate hemihydrate remained substantially unchanged after 36 months of storage at 25 ° C and under a relative humidity of 60%, at 30 ° C and under a relative humidity of 65% , as well as after 6 months at a temperature of 40 ° C with a relative humidity of 75%, and also after 6 months under refrigeration at a temperature between 5 ° C and 8 ° C. At this temperature the temperature was not observed. occurrence of turbidity or precipitates.
  • Table 1 shows the stability data corresponding to the contents of ibuprofen, L-arginine and codeine phosphate hemihydrate: Table 1
  • the active substances were analyzed by means of HPLC techniques.
  • Example 2 The composition obtained in Example 1 was also subjected to a photostability test according to the above-mentioned method, observing that the contents of ibuprofen, arginine and codeine phosphate hemihydrate remained substantially unchanged in the bulk solution after said test, as shown in Table 2:
  • Purified water is.
  • Purified water is.
  • Purified water is.

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  • Hospice & Palliative Care (AREA)
  • Immunology (AREA)
  • Psychiatry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une nouvelle composition pharmaceutique liquide qui contient de l'ibuprofène sous forme de sel comprenant un acide aminé basique et de la codéine ou un sel de codéine acceptable sur le plan pharmaceutique, à administrer par voie orale; ladite composition contenant en particulier un sel d'ibuprofène avec un acide aminé basique de type arginine, lysine ou des mélanges associés. L'invention concerne également un procédé pour préparer ladite composition pharmaceutique, ainsi que son utilisation, de préférence en pédiatrie, pour la fabrication d'un médicament utile dans le traitement de la douleur modérée à grave, l'inflammation, la fièvre et/ou autres affections dans lesquelles on utilise généralement de l'ibuprofène et/ou de la codéine, principalement en tant qu'analgésique. La composition de l'invention offre une bonne stabilité après avoir été soumise pendant trois ans à différentes conditions de température et d'humidité relative.
PCT/ES2010/000078 2010-03-01 2010-03-01 Composition pharmaceutique liquide d'ibuprofène et de codéine à administrer par voie orale, son procédé de préparation et son utilisation WO2011107617A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/ES2010/000078 WO2011107617A1 (fr) 2010-03-01 2010-03-01 Composition pharmaceutique liquide d'ibuprofène et de codéine à administrer par voie orale, son procédé de préparation et son utilisation
GB1215436.5A GB2490840B (en) 2010-03-01 2010-03-01 Liquid ibuprofen/codeine pharmaceutical composition for oral administration, the method for preparation thereof and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/ES2010/000078 WO2011107617A1 (fr) 2010-03-01 2010-03-01 Composition pharmaceutique liquide d'ibuprofène et de codéine à administrer par voie orale, son procédé de préparation et son utilisation

Publications (1)

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WO2011107617A1 true WO2011107617A1 (fr) 2011-09-09

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WO (1) WO2011107617A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3005262A1 (fr) * 2013-05-02 2014-11-07 Philippe Gorny Nouvelles compositions pharmaceutiques ou dietetiques permettant de masquer totalement l'amertume des sels d'arginine donnes a haute dose, sous forme liquide ou semi-liquide.

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0388125A1 (fr) * 1989-03-14 1990-09-19 Beecham Group Plc Médicament
CA2030140A1 (fr) * 1989-11-17 1991-05-18 Manfred Lohner Preparations medicamenteuses contenant un sel metallique d'ibuprofene et procede de fabrication desdites preparations
US5164398A (en) * 1991-04-01 1992-11-17 Merck & Co., Inc. Ibuprofen-antitussive combinations
WO1995007103A1 (fr) * 1993-09-07 1995-03-16 The Procter & Gamble Company Compositions contenant un sel d'acide amine d'un agent anti-inflammatoire non steroidien a base d'acide propionique et au moins un decongestionnant ou un expectorant ou un antihistaminique ou un antitussif
EP1226831A1 (fr) * 2001-01-30 2002-07-31 Leandro Baiocchi Solutions pharmaceutiques aqueuses de sels d'acide glycyrrhizique trisubstitués

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0388125A1 (fr) * 1989-03-14 1990-09-19 Beecham Group Plc Médicament
CA2030140A1 (fr) * 1989-11-17 1991-05-18 Manfred Lohner Preparations medicamenteuses contenant un sel metallique d'ibuprofene et procede de fabrication desdites preparations
US5164398A (en) * 1991-04-01 1992-11-17 Merck & Co., Inc. Ibuprofen-antitussive combinations
WO1995007103A1 (fr) * 1993-09-07 1995-03-16 The Procter & Gamble Company Compositions contenant un sel d'acide amine d'un agent anti-inflammatoire non steroidien a base d'acide propionique et au moins un decongestionnant ou un expectorant ou un antihistaminique ou un antitussif
EP1226831A1 (fr) * 2001-01-30 2002-07-31 Leandro Baiocchi Solutions pharmaceutiques aqueuses de sels d'acide glycyrrhizique trisubstitués

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GB201215436D0 (en) 2012-10-17
GB2490840A (en) 2012-11-14

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